0031-3998/08/6305-0497 Vol. 63, No. 5, 2008 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2008 International Pediatric Research Foundation, Inc. Biomaterial Scaffolds in Pediatric Tissue Engineering MINAL PATEL AND JOHN P. FISHER Fischell Department of Bioengineering, University of Maryland, College Park, Maryland 20742 ABSTRACT: This article reviews recent developments and major immune system is not completely developed. However, pedi- issues in the use and design of biomaterials for use as scaffolds in atric patients have exhibited a higher regenerative capacity com- pediatric tissue engineering. A brief history of tissue engineering and pared with adults because younger cells have undergone less the limitations of current tissue-engineering research with respect to stress and age damage. This review studies novel biomaterials as pediatric patients have been introduced. An overview of the charac- scaffolds and pediatric tissue-engineering applications. teristics of an ideal tissue-engineering scaffold for pediatric applica- tions has been presented, including a description of the different types of scaffolds. Applications of scaffolds materials have been high- CHARACTERISTICS OF AN IDEAL SCAFFOLD lighted in the fields of drug delivery, bone, cardiovascular, and skin tissue engineering with respect to the pediatric population. This Before developing a scaffold for any tissue-engineering review highlights biomaterials as scaffolds as an alternative treatment application, the material and biologic properties have to be method for pediatric surgeries due to the ability to create a functional evaluated. Initially, depending upon the application, mechan- cell-scaffold environment. (Pediatr Res 63: 497–501, 2008) ical properties should be studied keeping in mind the sur- rounding environment of the scaffold once placed in an in vivo he field of tissue engineering involves replacement of system. For example, while developing a scaffold for the Tdamaged or diseased tissue to maintain or improve tissue mandible bone; the mechanical properties have to be consid- function. Both engineering and biologic principles are applied ered as it is one of the strongest bones (12). However, for the to achieve this goal (1–3). Over the years, tissue engineering orbital bone which is 0.5 mm thick the mechanical properties has evolved from engineering organ tissue to mimicking do not play a role in scaffold design as it does not bear a large cellular function. Biomaterials play an important role in ad- mechanical load (13). Scaffold evaluation also includes study- vancing the field of tissue engineering and have resulted from ing the correct degradation rate, which is important because as a marriage of disciplines including life sciences, medicine, the scaffold degrades it is replaced by natural tissue. Depend- materials science, and engineering. Biomaterials are not new; ing upon the type of tissue to be replaced, the degradation rate throughout history there are references to glass eyes and can be controlled by changing the physical or chemical scaf- wooden or gold-filled teeth (4–6). A relatively new develop- fold properties. Scaffold degradation rate also influences the ment, however, is the close working relationships between the creation of degradation by-products, which may interfere with above-mentioned disciplines. Biomaterials are regarded as the tissue repair process by obstructing tissue growth or natural or synthetic materials used to replace part of a living causing inflammation (14,15). Scaffold porosity is also impor- system or to function in intimate contact with living tissue. tant to promote cell proliferation and differentiation and also They can serve as a scaffold designed to replace, repair, and for exchange of nutrients and metabolites. The surface prop- sustain organ structures. In the past decade, numerous scaf- erties and the ability to mold the scaffold into a specific folds have been developed for a variety of tissue-engineering construct are also critical, and depend upon the specific ap- applications (7–11). However, limitations of the scaffolds plication. For example, bone tissue engineering typically re- involve mechanical material failure, material-associated infec- quires a cube or disc-shaped scaffold (16). Nerve, vascular, tion, and immunogenic reaction to implanted materials. Keep- and trachea tissue engineering usually requires tube-shaped ing in mind these limitations, scaffolds designed for pediatric scaffolds (17). Skin, intestine, and liver tissue engineering applications require further modifications. Over the lifetime of generally require scaffolds in the form of a flat matrix (18). a pediatric patient, the material would have to grow and Scaffolds are also available in the form of injectable gels, remodel itself with the changing physiologic and biologic which can be used to fill irregularly shaped defects (19). Once environments. Moreover, after implantation the pediatric pa- the material properties of the scaffold have been characterized, tient would be further susceptible to foreign material as the further biologic testing is required. This includes studying the immune and foreign body reactions, and the implementation of different cells or growth factors to enhance the properties of Received November 1, 2007; accepted December 6, 2007. the scaffold. For pediatric applications, scaffolds should be Correspondence: John P. Fisher, Ph.D., Fischell Department of Bioengineering, University of Maryland, 3238 Jeong H. Kim Engineering Building (No. 225), College biocompatible, biodegradable, nonimmunogenic, and non- Park, Maryland 20742; e-mail: jpfi[email protected] or http://www.ench.umd.edu/ toxic. They should successfully promote cell growth, differ- ϳjpfisher entiation, attachment, and migration and be responsive to This work was supported by the State of Maryland Department of Business and Economic Development and the National Science Foundation through a CAREER growth and development changes. Finally, they should be easy Award (J.P.F., BES 0448684). to manufacture, sterilize, and microsurgically implant. 497 498 PATEL AND FISHER TYPES OF SCAFFOLDS vascular scaffold with the potential of repair, remodeling, and growth for pediatric cardiovascular tissue-engineering appli- Natural scaffolds. Natural scaffolds are made up of protein cations. Biodegradable tubular scaffolds were constructed or carbohydrates with particular biochemical, mechanical, and from polyglycolic acid mesh coated with a copolymer of poly structural properties. They can be derived from plant or animal [epsilon-caprolactone-L-lactide]. The scaffolds were seeded sources, and are mostly found to be both biocompatible and with a mixed population of smooth muscle cells and endothe- biodegradable. These scaffolds have an increased advantage lial cells cultured from ovine bone marrow-derived vascular due to the presence of multifunctional groups on scaffold cells. These autologous venous conduits were implanted in surfaces, which can be tailored according to specific applica- juvenile lambs and were evaluated up to 30 d postsurgically. tions. For example, collagen, chitosan, hyaluronic acid, fibrin, Results indicated the scaffold was unobstructed and no evi- and gelatin are all natural scaffolds, which have been applied dence of thrombosis was noted. Histologic results demon- for the repair and reconstruction of tissues (20–24). Porcine strated that the scaffold wall was composed of neo-tissue made collagen is a commercially available graft, which has been up of residual polymer matrix, mesenchymal cells, and extra- previously used as a tissue-engineering scaffold. It has also cellular matrix without evidence of calcification (28). Several been applied in a pediatric patient to close the anterior abdominal other research groups have developed synthetic materials for wall after a surgical procedure. The graft was in the form of a pediatric tissue-engineering applications (29–32). sheet, acellular and did not provoke an immune response. After Hydrogels. Hydrogels are made up of polymer chains, 18 mo, the wound had healed and the collagen graft was suc- which swell in an aqueous solution, and can be natural or cessfully applied for abdominal wall reconstruction (25). synthetic in nature. Hydrogels are typically fabricated with Hyalomatrix composed of silicone and hyaluronic acid has thermally, chemically, or photochemically induced radical been previously used to treat pediatric burn patients (26). They initiators, forming a covalently bound polymer network (33– successfully covered the dermal plane and actively stimulated 35). These gels are often designed to be biodegradable, as they spontaneous healing. The matrix had a slow degradation rate can be degraded within the body by water or natural enzymes compared with the current treatment methods and as a result and ultimately absorbed. Hydrogels are typically biocompat- provided a sufficient time frame for complete wound healing. ible, owing to their large water content, as they do not provoke Recently, human fibrin was used as a scaffold to culture an immune response and cause inflammation. Thus, hydrogels pediatric auricular chondrocytes to engineer elastic cartilage. have been found to possess tissue-like properties as they can Gene expression studies demonstrated that the engineered be successfully used to encapsulate cells and create a cell- cartilage resembled the features of native elastic cartilage and scaffold environment (36,37). Hydrogels can also be used in could be applied as a scaffold for pediatric